Genital Herpes Simplex Virus (HSV) infection is a disease of major public health importance. Its frequent recurrence rate, its complications of meningitis, and radicultis, and its association with neonatal morbidity and cervical cancer make studies of the natural history, immunology and therapy of HSV of broad interest. We propose to study the natural history, immunology and therapy of HSV of broad interest. We propose to study the natural history of genital HSV infection, to determine whether the disease changes in character or rate of recurrence over time. We will systematically obtain clinical epidemiologic information and perform virus isolation on all cases, and will obtain detailed virologic and immunologic data on selected cases to define host factors and type or strain specific viral factors which may influence the clinical manifestations, severity and risk of latency and of recurrence. Because we have determined that genital HSV-1 infections recur less often than genital HSV-2 infections, we will compare cellular, humoral and local immune responses of primary HSV-2 vs. primary HSV-1 infection to determine whether differences in immune response to these types are related to differences in the recurrence rates of genital disease. We will prospectively follow exposed sexual partners to define the risk of transmitting genital HSV and define the role asymptomatic shedding of virus plays in this process. Restriction enzyme analysis of HSV strains will also be employed to assess the contribution of exogenous reinfection to recurrent disease. The effect of prenancy on the severity and recurrence rate of genital HSV disease and the natural history of pharyngeal and rectal HSV will also be studied. Pilot studies to define the prevalence and incidence of disease in specific populations will be undertaken.